Trudeau Institute, Saranac Lake, NY.
Computational Biology and Genomics Core, Laboratory of Genetics and Genomics, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, MD.
Immunohorizons. 2023 Aug 1;7(8):562-576. doi: 10.4049/immunohorizons.2200066.
To determine the impact of accumulating Ag exposure on immunity in the aging mouse, and to develop a model more relevant to humans who are exposed to multiple pathogens during life, we sequentially infected young female mice with four distinct pathogens at 8-wk intervals: murine γ-herpesvirus 68, Sendai virus, murine CMV, and Heligmosomoides polygyrus. Mock-infected mice received PBS. After aging the sequentially infected and mock-infected mice to 18-25 mo under specific pathogen-free conditions, we analyzed multiple immune parameters. We assessed transcriptional activity in peripheral blood, T cell phenotype, the diversity of influenza epitopes recognized by CD8 T cells, and the response of the animals to infection with influenza virus and Mycobacterium tuberculosis. Our data show enhanced transcriptional activation in sequentially infected aged mice, with changes in some CD8 T cell subsets. However, there was no measurable difference in the response of mock-infected and sequentially infected aged mice to de novo infection with either influenza virus or M. tuberculosis at 18-21 mo. Unexpectedly, a single experiment in which 25-mo-old female mice were challenged with influenza virus revealed a significantly higher survival rate for sequentially infected (80%) versus mock-infected (20%) mice. These data suggest that although exposure to a variety of pathogen challenges in the mouse model does not overtly impact cellular markers of immunity in aged female mice following de novo respiratory infection, subtle changes may emerge in other compartments or with increasing age.
为了确定 Ag 暴露积累对衰老小鼠免疫的影响，并开发出一种与一生中暴露于多种病原体的人类更相关的模型，我们以 8 周的间隔顺序感染年轻雌性小鼠四种不同的病原体：鼠γ疱疹病毒 68、仙台病毒、鼠巨细胞病毒和旋毛虫。模拟感染的小鼠接受 PBS。在特定病原体条件下将顺序感染和模拟感染的小鼠衰老至 18-25 个月后，我们分析了多种免疫参数。我们评估了外周血中的转录活性、T 细胞表型、CD8 T 细胞识别的流感表位的多样性以及动物对流感病毒和结核分枝杆菌感染的反应。我们的数据显示，顺序感染的衰老小鼠的转录激活增强，一些 CD8 T 细胞亚群发生变化。然而，在 18-21 个月时，模拟感染和顺序感染的衰老小鼠对新感染的流感病毒或结核分枝杆菌的反应没有可测量的差异。出乎意料的是，一项对 25 个月大的雌性小鼠进行流感病毒挑战的实验表明，与模拟感染（20%）的小鼠相比，顺序感染（80%）的小鼠的存活率显著更高。这些数据表明，尽管在小鼠模型中暴露于多种病原体挑战不会明显影响新发生呼吸道感染后衰老雌性小鼠免疫的细胞标志物，但在其他部位或随着年龄的增长可能会出现微妙的变化。
